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1.
Int J Biochem Cell Biol ; 81(Pt B): 323-334, 2016 12.
Article in English | MEDLINE | ID: mdl-27592449

ABSTRACT

Sepsis-induced myocardial dysfunction is associated with increased oxidative stress and mitochondrial dysfunction. Current evidence suggests a protective role of thioredoxin-1 (Trx1) in the pathogenesis of cardiovascular diseases. However, it is unknown yet a putative role of Trx1 in sepsis-induced myocardial dysfunction, in which oxidative stress is an underlying cause. Transgenic male mice with Trx1 cardiac-specific overexpression (Trx1-Tg) and its wild-type control (wt) were subjected to cecal ligation and puncture or sham surgery. After 6, 18, and 24h, cardiac contractility, antioxidant enzymes, protein oxidation, and mitochondrial function were evaluated. Trx1 overexpression improved the average life expectancy (Trx1-Tg: 36, wt: 28h; p=0.0204). Sepsis induced a decrease in left ventricular developed pressure in both groups, while the contractile reserve, estimated as the response to ß-adrenergic stimulus, was higher in Trx1-Tg in relation to wt, after 6h of the procedure. Trx1 overexpression attenuated complex I inhibition, protein carbonylation, and loss of membrane potential, and preserved Mn superoxide dismutase activity at 24h. Ultrastructural alterations in mitochondrial cristae were accompanied by reduced optic atrophy 1 (OPA1) fusion protein, and activation of dynamin-related protein 1 (Drp1) (fission protein) in wt mice at 24h, suggesting mitochondrial fusion/fission imbalance. PGC-1α gene expression showed a 2.5-fold increase in Trx1-Tg at 24h, suggesting mitochondrial biogenesis induction. Autophagy, demonstrated by electron microscopy and increased LC3-II/LC3-I ratio, was observed earlier in Trx1-Tg. In conclusion, Trx1 overexpression extends antioxidant protection, attenuates mitochondrial damage, and activates mitochondrial turnover (mitophagy and biogenesis), preserves contractile reserve and prolongs survival during sepsis.


Subject(s)
Gene Expression , Mitochondria/genetics , Myocardium/metabolism , Sepsis , Thioredoxins/genetics , Thioredoxins/metabolism , Animals , Antioxidants/metabolism , Male , Mice , Mice, Transgenic , Mitochondria/metabolism , Mitochondria/pathology , Mitochondrial Diseases/genetics , Myocardium/pathology , Real-Time Polymerase Chain Reaction , Sepsis/physiopathology
2.
Antioxid Redox Signal ; 15(9): 2395-406, 2011 Nov 01.
Article in English | MEDLINE | ID: mdl-21529143

ABSTRACT

AIMS: Obesity arises on defective neuroendocrine pathways that increase energy intake and reduce mitochondrial metabolism. In the metabolic syndrome, mitochondrial dysfunction accomplishes defects in fatty acid oxidation and reciprocal increase in triglyceride content with insulin resistance and hyperglycemia. Mitochondrial inhibition is attributed to reduced biogenesis, excessive fission, and low adipokine-AMP-activated protein kinase (AMPK) level, but lateness of the respiratory chain contributes to perturbations. Considering that nitric oxide (NO) binds cytochrome oxidase and inhibits respiration, we explored NO as a direct effector of mitochondrial dysfunction in the leptin-deficient ob/ob mice. RESULTS: A remarkable three- to fourfold increase in neuronal nitric oxide synthase (nNOS) expression and activity was detected by western blot, citrulline assay, electronic and confocal microscopy, flow cytometry, and NO electrode sensor in mitochondria from ob/ob mice. High NO reduced oxygen uptake in ob/ob mitochondria by inhibition of complex IV and nitration of complex I. Low metabolic status restricted ß-oxidation in obese mitochondria and displaced acetyl-CoA to fat synthesis; instead, small interference RNA nNOS caused a phenotype change with fat reduction in ob/ob adipocytes. INNOVATION: We evidenced that leptin increases mitochondrial respiration and fat utilization by potentially inhibiting NO release. Accordingly, leptin administration to ob/ob mice prevented nNOS overexpression and mitochondrial dysfunction in vivo and rescued leptin-dependent effects by matrix NO reduction, whereas leptin-Ob-Rb disruption increased the formation of mitochondrial NO in control adipocytes. We demonstrated that in ob/ob, hypoleptinemia is associated with critically low mitochondrial p-AMPK and that, oppositely to p-Akt2, p-AMPK is a negative modulator of nNOS. CONCLUSION: Thereby, defective leptin-AMPK pathway links mitochondrial NO to obesity with complex I syndrome and dysfunctional mitochondria.


Subject(s)
Adenylate Kinase/metabolism , Leptin/pharmacology , Mitochondria/drug effects , Mitochondria/metabolism , Nitric Oxide/metabolism , Obesity/metabolism , Animals , Blotting, Western , Fatty Acids/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Microscopy, Confocal , Microscopy, Electron , Mitochondria/ultrastructure , Nitric Oxide Synthase Type I/genetics , Nitric Oxide Synthase Type I/metabolism , RNA, Small Interfering , Signal Transduction/drug effects , Signal Transduction/genetics
3.
Clin Physiol Funct Imaging ; 30(6): 381-8, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20726996

ABSTRACT

The high mortality rate of cardiogenic shock in acute myocardial infarction (AMI) implies that debate over the correct haemodynamic management is still unresolved. The purpose of this review is to re-evaluate the reciprocal relationships between oxygen-related variables and response to treatment in a large number of patients with AMI. A MEDLINE search of reports published between 1970 and 2008 was performed. Twelve clinical reports including 453 patients with AMI and 989 sets of oxygen delivery and oxygen consumption expressed in ml min⁻¹ m⁻² and oxygen extraction ratio were selected. While processing this data, we found an early down-regulation in oxygen demand linked to a decrease in oxygen supply. This mechanism is also supported in some studies by a critically low oxygen uptake that was not associated with lactic acidosis.


Subject(s)
Myocardial Infarction/metabolism , Myocardium/metabolism , Oxygen Consumption , Oxygen/metabolism , Shock, Cardiogenic/etiology , Adaptation, Physiological , Aged , Aged, 80 and over , Hemodynamics , Humans , Middle Aged , Myocardial Infarction/complications , Myocardial Infarction/physiopathology , Myocardial Infarction/therapy , Oxygen Inhalation Therapy , Shock, Cardiogenic/metabolism , Shock, Cardiogenic/physiopathology , Shock, Cardiogenic/therapy
4.
Rev. argent. transfus ; 35(4): 247-252, 2009. graf
Article in Spanish | LILACS | ID: lil-665466

ABSTRACT

Nitric oxide (NO) is a fascinating ubiquitous molecule with multiple complex roles in biological systems, such as intra and inter cell communications. Endothelial physiology relies on its endothelium derived relaxing factor (EDRF) properties as originally described. NO exhibits physiological vasodilator effects, mediated in part by its binding to the heme group of guanylyl cyclase to produce cGMP that relaxes vascular smooth muscle by lowering cytoplasmic Ca2' levels. So me experiments from several laboratories have very recently established that red blood cells provide a novel vasodilator activity NO mediated in which hemoglobin acts as an O2 sensor and O2-responsive NO signal transducer, thereby regulating both peripheral and pulmonary vascular tone. Haemoglobin through its oxygen binding function adjusts NO bioavailability at the microcirculation and in turn, red blood cells can cause microvessels to dila­te or constrict, with S-nitroso-haemoglobin as an intermediate. But other groups demonstrated that SNO­Hb is not essential for the physiologic coupling of erythrocyte deoxygenation with increased NO bioactivity in vivo. A third group emphasized the role of nitrites and the nitrite reductase activity of hemoglobin as the source of vasodilators in the microcirculation. As blood transfusion in the setting of acute coronary syndromes seemed to be associated with higher mortality, some authors linked those phenomena to the S-nitrosohemoglobin deficiency in banked blood, a mechanism that could explain its loss of physiological activity. In adition to the peripheric actions, the regulatory function of NO on cardiac efficiency also contributes to its key role in the circulation.


Subject(s)
Blood Circulation , Nitric Oxide Synthase/blood , Nitric Oxide/blood , Hemoglobins , Microcirculation , Nitrites , Nitric Oxide Synthase/metabolism , Nitric Oxide/metabolism
5.
Front Biosci ; 12: 1041-8, 2007 Jan 01.
Article in English | MEDLINE | ID: mdl-17127359

ABSTRACT

In the last years, nitric oxide synthases (NOS) have been localized in mitochondria. At this site, NO yield directly regulates the activity of cytochrome oxidase, O(2) uptake and the production of reactive oxygen species. Recent studies showed that translocated neuronal nitric oxide synthase (nNOS) is posttranslationally modified including phosphorylation at Ser 1412 (in mice) and myristoylation in an internal residue. Different studies confirm that modified nNOS alpha is the main modulable isoform in mitochondria. Modulation of mtNOS was observed in different situations, like adaptation to reduced O(2) availability and hypoxia, adaptation to low environmental temperature, and processes linked to life and death by effects on kinases and transcription factors. We present here evidence about the role of mtNOS in the analyzed conditions.


Subject(s)
Mitochondria/enzymology , Nitric Oxide Synthase Type I/physiology , Adaptation, Physiological , Animals , Brain/embryology , Brain/enzymology , Brain/growth & development , Liver/embryology , Liver/enzymology , Liver/growth & development , Mice , Neuronal Plasticity , Oxygen/metabolism , Triiodothyronine/physiology
6.
J Biol Chem ; 281(8): 4779-86, 2006 Feb 24.
Article in English | MEDLINE | ID: mdl-16361261

ABSTRACT

Although transcriptional effects of thyroid hormones have substantial influence on oxidative metabolism, how thyroid sets basal metabolic rate remains obscure. Compartmental localization of nitric-oxide synthases is important for nitric oxide signaling. We therefore examined liver neuronal nitric-oxide synthase-alpha (nNOS) subcellular distribution as a putative mechanism for thyroid effects on rat metabolic rate. At low 3,3',5-triiodo-L-thyronine levels, nNOS mRNA increased by 3-fold, protein expression by one-fold, and nNOS was selectively translocated to mitochondria without changes in other isoforms. In contrast, under thyroid hormone administration, mRNA level did not change and nNOS remained predominantly localized in cytosol. In hypothyroidism, nNOS translocation resulted in enhanced mitochondrial nitric-oxide synthase activity with low O2 uptake. In this context, NO utilization increased active O2 species and peroxynitrite yields and tyrosine nitration of complex I proteins that reduced complex activity. Hypothyroidism was also associated to high phospho-p38 mitogen-activated protein kinase and decreased phospho-extracellular signal-regulated kinase 1/2 and cyclin D1 levels. Similarly to thyroid hormones, but without changing thyroid status, nitric-oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester increased basal metabolic rate, prevented mitochondrial nitration and complex I derangement, and turned mitogen-activated protein kinase signaling and cyclin D1 expression back to control pattern. We surmise that nNOS spatial confinement in mitochondria is a significant downstream effector of thyroid hormone and hypothyroid phenotype.


Subject(s)
Electron Transport Complex I/metabolism , Hypothyroidism/pathology , Liver/enzymology , Nitric Oxide Synthase Type I/metabolism , Animals , Cyclin D1/metabolism , Cytosol/metabolism , Electrons , Electrophoresis, Polyacrylamide Gel , HSP90 Heat-Shock Proteins/metabolism , Hypothyroidism/metabolism , Immunoblotting , Immunoprecipitation , Liver/metabolism , MAP Kinase Signaling System , Male , Microscopy, Immunoelectron , Mitochondria/metabolism , Mitochondria, Liver/metabolism , Models, Chemical , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide Synthase/metabolism , Oxidants/metabolism , Oxygen/metabolism , Peroxynitrous Acid/chemistry , Phenotype , Protein Isoforms , Protein Transport , RNA, Messenger/metabolism , Rats , Rats, Wistar , Reactive Oxygen Species/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction , Subcellular Fractions/metabolism , Thyroid Hormones/metabolism , Transcription, Genetic , p38 Mitogen-Activated Protein Kinases/metabolism
7.
Mol Aspects Med ; 25(1-2): 125-39, 2004.
Article in English | MEDLINE | ID: mdl-15051322

ABSTRACT

Mitochondria are the specialized organelles for energy metabolism but also participate in the production of O(2) active species, cell cycle regulation, apoptosis and thermogenesis. Classically, regulation of mitochondrial energy functions was based on the ADP/ATP ratio, which dynamically stimulates the transition between resting and maximal O(2) uptake. However, in the last years, NO was identified as a physiologic regulator of electron transfer and ATP synthesis by inhibiting cytochrome oxidase. Additionally, NO stimulates the mitochondrial production of O(2) active species, primarily O(2)(-) and H(2)O(2), and, depending on NO matrix concentration, of ONOO(-), which is responsible for the nitrosylation and nitration of mitochondrial components. By this means, alteration in mitochondrial complexes restricts energy output, further increases O(2) active species and changes cell signaling for proliferation and apoptosis through redox effects on specific pathways. These mechanisms are prototypically operating in prevalent generalized diseases like sepsis with multiorgan failure or limited neurodegenerative disorders like Parkinson's disease. Complex I appears to be highly susceptible to ONOO(-) effects and nitration, which defines an acquired group of mitochondrial disorders, in addition to the genetically induced syndromes. Increase of mitochondrial NO may follow over-expression of nNOS, induction and translocation of iNOS, and activation and/or increased content of the newly described mtNOS. Likewise, mtNOS is important in the modulation of O(2) uptake and cell signaling, and in mitochondrial pathology, including the effects of aging, dystrophin deficiency, hypoxia, inflammation and cancer.


Subject(s)
Electron Transport Complex I/physiology , Mitochondria/physiology , Nitric Oxide Synthase/physiology , Nitric Oxide/physiology , Humans , Oxidative Stress/physiology , Parkinson Disease/physiopathology
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